Non-factor Therapies in Hemophilia: Mechanisms, Clinical Evidence, Patient Management, and Future Perspectives.

Hemophilia is an inherited bleeding disorder caused by deficiencies in coagulation factor VIII (FVIII) or factor IX (FIX), leading to impaired thrombin generation and recurrent bleeding episodes. For decades, prophylactic factor replacement therapy has been the mainstay of hemophilia management; however, its limitations-including treatment burden, inhibitor development, and incomplete bleeding control-have required the development of alternative therapeutic strategies. Non-factor therapies represent a major paradigm shift in hemophilia care by restoring hemostatic balance through mechanisms independent of FVIII or FIX replacement. These approaches include bispecific antibodies that mimic FVIII cofactor activity and rebalancing strategies that enhance thrombin generation by inhibiting anticoagulant pathways such as tissue factor pathway inhibitor or antithrombin. Clinical studies have demonstrated that non-factor therapies provide stable and predictable prophylactic efficacy, significantly reduce bleeding rates, and improve quality of life in people with hemophilia A or B, irrespective of inhibitor status. Despite these advances, important challenges remain. Non-factor therapies modify physiological coagulation pathways and may be associated with thrombotic events due to imbalance between procoagulant and anticoagulant mechanisms, particularly for rebalancing agents. In addition, the lack of standardized laboratory assays for assessing global coagulation potential, uncertainties regarding combination therapy during breakthrough bleeding or surgery, and concerns about long-term safety and cost burden could limit optimal implementation. This review summarizes the mechanisms of action, clinical evidence, and safety considerations of currently available and emerging non-factor therapies for hemophilia. We also discuss unmet clinical needs, patient management considerations, and future perspectives aimed at optimizing the safe and sustainable use of non-factor therapies into routine hemophilia care.